Research by a team led by Dr Elizabeth Fullam, has revealed new findings about an enzyme found in Mycobacterium tuberculosis (Mtb) the bacterium that causes TB.
TB causes more deaths than any other infectious disease, including
from HIV and malaria. In 2016 there were 10.4 million new cases of TB
and 1.7 million people died. The rise in cases of TB that are resistant
to the current therapies that are available means that there is an
urgent need to develop new TB therapeutics.
Mtb is a highly unique bacterium and is enclosed within a distinctive
cell wall that is comprised of unusual sugars and lipids which protect
the bacteria from the host environment. Disruption of essential pathways
involved in the assembly of the Mtb cell wall is an attractive approach
for new TB drugs.
The team found a key structural motif in the tuberculosis
N-acetylglucosamine-6-phosphate deacetylase (NagA) enzyme. Attacking
this structural motif through the design and exploitation of new
molecules will enable scientists to inhibit this critical pathway and
kill TB.
Using the X-ray facilities at the Diamond Light Source, Harwell, they
were provided with detailed molecular insights into how the NagA enzyme
generates important precursors that are involved in Mtb cell wall
biosynthesis and metabolism.
Dr Fullam, who is a Sir Henry Dale Fellow at the University of
Warwick's School of Life Sciences, said: "Tuberculosis is a major global
health problem and the current drugs that we use today are over 40
years old. It is therefore vital that we discover new therapeutic agents
to combat TB. In our studies, we have investigated the role of an
enzyme in Mtb called NagA. This enzyme is a promising drug target as it
is at a crucial metabolic chokepoint in Mtb. This means that a molecule
that stops the enzyme from working would be an effective strategy for a
drug and therefore it is critical to understand its function.
"Our group has identified a weak point within this protein that we
can target and will now enable us to design specific molecules to block
its function"
Using a range of biochemical and biophysical checks to determine the
substrate specificity for the Mtb NagA enzyme they found a unique
structural feauture in the Mtb NagA enzyme.This has revealed a molecular
image of the protein and provides a platform to allow scientists to
design new drugs that will hopefully inhibit this vital pathway and kill
TB.
The research 'Structural and functional determination of homologs of the Mycobacterium tuberculosis N-acetylglucosamine-6-phosphate deacetylase (NagA)' is published in the Journal of Biological Chemistry
Story Source:
https://warwick.ac.uk/newsandevents/pressreleases/enzyme_discovery_could/" rel="nofollow - Materials provided by http://www.warwick.ac.uk" rel="nofollow - University of Warwick . Note: Content may be edited for style and length.